1. What is the Optimal Approach to CLL, BR vs. FCR/FR?
Michael J. Keating
MD Anderson Cancer Center
Presented by:
Richard R. Furman
Weill Cornell Medical College

2. Bendamustine Bifunctional Antineoplastic Agent
CH3 N
ClH2C N N
CO2H
Purine-like Benzimidazole Ring
ClH2C
Alkylating Group
Available in Germany,
Unique in vitro anti-tumor profile
Rummel M, J Clin Oncol. 2005;23:3383. 2

3. Fludarabine + Prednisone (1983 – 1993) Progression Free Survival
Median PFS: 26 months
Proportion

4. Long Term Outcomes for FR: CALGB 9712
Months
Survival

5. Chlorambucil vs. Bendamustine in Untreated CLL: Progression-Free Survival
Knauf WU. JCO. 2009; 27:4378 5

6. GCLLSG CLL2M: BR in Untreated CLL
Treatment:
Bendamustine 90 mg/m2 days 1,2 (cycles 1-6)
Rituximab: 375 mg/m2 (cycle 1)
500 mg/m2 (cycles 2-6)
Study Characteristics:
117 patients
No age limit (median=64; range 34-78)
73.5% received all 6 cycles
Fischer K. JCO 2012; 30:3209.

7. CLL2M: BR in Untreated CLL: Event Free Survival
median EFS = 33.9 months
Fischer K. JCO 2012; 30:3209.

8. CLL2M: BR in Untreated CLL:
Response Rates
Response
N=124 %
ORR
103
88.0 CR 27
23.1
nPR 2
1.7 PR 74
63.2 SD 11
9.4 PD -
Fischer K. JCO 2012; 30:3209.

9. BR: Adverse Events, Grades 3+4 (pts)
Hematologic Toxicities:
26.5
25.6
Leucopenia
15.4
14.5
Neutropenia
10.3
9.4
Thrombocytopenia
7.7
Anemia
4.3
Tumor lysis syndrome
2.6
Allergic reaction
8.5
0.9
Infectious
6.8
Other non-hematologic
18.8

10. Phase III Trial of FC + / - Rituximab in Untreated CLL: GCLLSG CLL8 Trial
Fludarabine 25 mg/m2, d1-3
Cyclophosphamide 250 mg/m2, d1-3
RANDOMI ZE F O L W U P
Untreated
No age restriction
Active CLL requiring therapy
x 6 cycles
Fludarabine 25 mg/m2, d1-3
Cyclophosphamide 250 mg/m2, d1-3
Rituximab 500 mg/m2, d1 (375 mg/m2 initial dose)
(n = 817)
Primary endpoint: PFS
No age limit
74% of patients received all 6 courses of FCR
Hallek M. Lancet 2010; 376:1164

11. FCR vs. FC in Untreated CLL: GCLLSG CLL8 Trialp
PFS
51.8 m
32.8 m
< .001
ORR
95.1%
88.4%
.001 CR
44.1%
21.8% PR
51%
66.6%
< .01
OS (3yr)
87%
83%
.01
Hallek M. Lancet 2010; 376:1164

12. GCLLSG CLL8: FCR vs. FC Progression Free Survival
0.0
0.2
0.6
0.8
1.0
0.4
Cumulative Survival
Median PFS: FCR 57 months
FC months
Median follow-up:
5.9 years
Fischer K. ASH 2012.

13. CLL8: Adverse Events (pts)
Hallek M. Lancet 2010; 376:1164

14. Response Comparison Response BR (%) FCR (%) ORR 88.0 95.1 CR 23.1 44.1PR
64.9
51.0
Median PFS
33.9 mo
57.0 mo

15. AE Comparison Adverse Event BR (%) FCR (%) Hematologic Toxicity 52.196
Neutropenia
19.7 55
Thrombocytopenia
22.2 18
Anemia 12
Infections
7.7 46
Tumor Lysis Syndrome
2.6 1

16. Patient Comparison Characteristic BR (%) FCR (%) Age > 65 48.7 31
Binet Stage C
46.2
IgVH unmutated
61.8 63
Del 11q / 17p
26.4 34
Zap-70+
15.7 42

17. Patient Comparison Characteristic BR (%) FCR (%) Age > 65 48.7 31
Binet Stage C
46.2
IgVH unmutated
61.8 63
Del 11q / 17p
26.4 34
Zap-70+
15.7 42

18. FCR300: First-line Outcomes
Department of Leukemia
UT MD Anderson Cancer Center
Houston, TX

19. Response to FCR (NCI-WG: 300 Patients)
# of Pts
(%)
ORR
285 95 CR
217 72
nPR 31 10 PR 37 12
No response 13 4
Early death 2 1

20. FCR300: PFS and OS
P<.0001
Proportion Surviving
PFS OS
Months

21. FCR300: PFS by IGHV Mutation Status
Group Events Total
IGHV-M
IGHV-UM
Unknown
Proportion Progression-free
P<.0001
Months

22. FCR vs. BR: The Tally FCR BR Duration of follow up ORR CR PFS
Toxicity Profile

23. CLL10 GCLLSG: Randomized Trial of FCR vs. BR ASH 2013?
fludarabine 25 mg/m2 d1-3 cyclophosphamide 250 mg/m2 d1-3
rituximab 375 mg/m2 C1, d1
500 mg/m2 C2-6, d1
Primary Endpoint:
2 yr
Untreated CLL (N = 564)
Randomize
bendamustine 90 mg/m2 d1,2
rituximab 375 mg/m2 C1, d1
500 mg/m2 C2-6, d1 23 23